The Allostatic Reset Model (ARM) of Psychedelic Action

Despite being induced by a transient pharmacological exposure, psychedelic experiences can catalyze enduring psychological transformation, presenting a central challenge for understanding the mechanism of action of psychedelic medicines. To address this challenge, the Allostatic Reset Model (ARM) of psychedelic action is proposed, which conceptualizes psychedelic therapeutic effects as a staged, multi-system adaptive stress process unfolding across the following interacting domains: autonomic physiology, neurophysiology, epigenetics, psychological transformation, and narrative meaning-making. In this model, psychedelic administration initiates a perturbation of homeostasis characterized by acute sympathetic activation, psychological challenge, increased neural entropy, and destabilization of relevant neural and cognitive regularities. Subsequently, a coordinated compensatory response emerges, marked by parasympathetic engagement and heightened multi-system plasticity. During this concluding phase, psychological flexibility and integrative meaning-making parallel structural and functional recalibration across systems. We associate this sub-acute period of relative quiescence with the ‘after glow’ of a psychedelic experience, analogous to a ‘calm after a storm’. Epigenetic changes in the brain further facilitate durable biological change. ARM leverages cross-disciplinary frameworks, including hormesis, rebound, supercompensation, and the ‘Hero’s Journey’ archetype to furnish a new model of the therapeutic action of psychedelics integrating acute autonomic and psychological stress with a compensatory, adaptive multi-system regulatory response.